This document discusses post-authorization safety studies (PASS) and ongoing safety surveillance. It provides background on the legal basis and guidelines for PASS from the EMA and ICH. It notes that about 25% of products under additional monitoring by EMA have PASS requirements. The number of studies registered in the EU PAS register has risen significantly in recent years. PASS can be either imposed as an obligation or conducted voluntarily. Key differences between PASS and pre-approval studies are also outlined. The role and significance of PASS is increasing as a way to decrease drug development costs and times while increasing the collection of real-world data.

1. POST-AUTHORISATION
SAFETY STUDIES
MAGDALENA MATUSIAK
PHARMACOVIGILANCE TEAM LEAD, KCR
IS THE ONGOING
SURVEILLANCE
A BLESSING OR A CURSE?

2. 2
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3. 3
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TYPE OF FINANCIAL INTEREST WITHIN LAST 12 MONTHS NAME OF COMMERCIAL INTEREST
GRANTS/RESEARCH FUNDING
STOCK SHAREHOLDER
CONSULTING FEES
EMPLOYEE
OTHER (RECEIPT OF INTELLECTUAL PROPERTY RIGHTS/PATENT
HOLDER, SPEAKER’S BUREAU)

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BROADER PERSPECTIVE – BETTER OUTCOMES
Innovation in the PASS concept

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PASS - LEGAL BASIS AND GUIDELINES
EMA GVP Module VIII
Post-Authorization Safety Studies
(legal basis: Directive 2010/84/EU (amending Directive 2001/83/EC)
2012
2013
2015
2016 Q1
FIRST
VERSION
CAME INTO
EFFECT
REVISION 1
CAME INTO
EFFECT
DRAFT REVISION
2 - PUBLIC
CONSULTATIONS
REVISION 2
- ANTICIPATED
DATE FOR
COMING
INTO EFFECT

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PASS - PART OF ADDITIONAL MONITORING
• Almost 300 products on the current EMA list of medicinal products under
additional monitoring (status of February 2016)
• About 25% of listed products under PASS
• About 100 medicinal products listed in April 2013
Source: Inspections & Human Medicines Pharmacovigilance EMA/245297/2013
Rev.31, 24 February 2016

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PASS – ENCEPP (EU PAS) REGISTER
• The number of studies registered in the ENCePP (EU PAS) register has
risen from 440 to 690 (56% increase) between January and December
2015
Source: EMA/847196/2015 ENCePP activity report 2015; 8 march 2016
9
27
48
74
103
0
27,5
55
82,5
110
2011 2012 2013 2014 2015
Number of new studies
registered
by ENCePP Centres

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PASS - LEGAL BASIS AND GUIDELINES
ICH Guidelines E2A-E2F
ISPE, Good Pharmacoepidemiology Practices
Guidance for the format and content of the protocol of non-interventional post-authorization safety studies
Guidance for the format and content of the final study report of non-interventional post-authorisation safety studies
ENCePP, Guide on methodological standards in pharmacoepidemiology
Guidelines on Good Pharmacovigilance Practices
Good Clinical Practice

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PASS - REQUIREMENTS AND SUPPORT
METHODOLOGICAL APPROACH
REAL-WORLD OUTCOMES
TRANSPARENCY
PRAC ASSESSMENT
EU PAS REGISTER
LONG-TERM SAFETY
SURVEILLANCE
SCIENTIFIC STUDY PROTOCOL
EVIDENCE-BASED REPORT
EFFECTIVE SAFETY
COMMUNICATION
QUALITY AND INTEGRITY OF
DATA
DIFFERENCES IN COUNTRY
SPECIFIC REQUIREMENTS
SCIENTIFIC GUIDELINES
PUBLIC CONSULTATIONS
PUBLIC HEARINGS
SCIENTIFIC ADVICE FOR
PASS
ADAPTIVE PATHWAYS
INCREASING
REQUIREMENTS
INCREASING
CHALLENGES
INCREASING
REGULATORY
SUPPORT

10. PASS PASS
IMPOSED
VOLUNTARY
CLINICAL TRIAL PHASE IV
NON-INTERVENTIONAL STUDY
PASS – STANDARD TYPES
10

11. STUDIES IMPOSED
AS AN OBLIGATION
STUDIES CONDUCTED
VOLUNTARILY
MANDATORY FORMAT OF THE STUDY PROTOCOL AND REPORT REQUIRED GVP RECOMMENDATION
STUDY PROTOCOL AND REPORT SUBMISSION TO NCA/EMA REQUIRED REQUIRED
QPPV INVOLVEMENT IN THE REVIEW AND SIGN-OFF OF STUDY
PROTOCOLS
REQUIRED REQUIRED
REGISTRATION OF STUDY IN EU PAS REGISTER REQUIRED GVP RECOMMENDATION
PHARMACOVIGILANCE SYSTEM REQUIRED REQUIRED
ENCePP CODE OF CONDUCT RECOMMENDED RECOMMENDED
EMA SCIENTIFIC ADVICE OPTIONAL STRONGLY
RECOMMENDED
PASS – IMPOSED VS VOLUNTARY
11

12. CLINICAL DATA REAL LIFE DATA
HOMOGENOUS PATIENTS
(INCLUSION/EXCLUSION CRITERIA)
EXPECTED RESPONSE WITHIN PRE-
DEFINED MARGIN
CAREFUL DATA VERIFICATION, STRICT
STATISTICAL REGIME
DEFINED INDICATION/DOSAGE REGIMEN
LIMITED TIME-FRAMES
HETEROGENOUS BIG POPULATION
VARIABILITY IN RESPONSE
MISSING DATA, STATISTICAL ANALYSIS
CHALLENGES
PRESCRIBED IN USUAL MANNER/OFF
LABEL USE
LONG-TERM SAFETY
PASS VS PRE-APPROVAL
12

13. DECREASING THE TIME
AND COSTS OF CLINICAL
DEVELOPMENT
INCREASING THE ROLE
OF REAL-LIFE DATA COLLECTED
DURING POST-AUTHORISATION
RESEARCH
PASS - INCREASING SIGNIFICANCE
13

14. • Biosimilar monoclonal antibody – EMA scientific advice (before start of
the clinical development)
INITIAL PROPOSITIONS EMA ADVICE
EXTENSIVE PRE-CLINICAL RESEARCH SIGNIFICANT REDUCTION OF ANIMALS’ NUMBER
AND TIME OF RESEARCH
PHASE 1 STUDY ONE PIVOTAL CLINICAL TRIAL WITH ELEMENTS
OF PHASE 1 INCORPORATED INTO PHASE 3
STUDY, PROVIDED THAT RMP/PASS IS
APPROPRIATELY DESIGNED AT THE MOMENT OF
MA APPLICATION
PHASE 2 STUDY
PHASE 3 STUDY
PASS - CASE STUDY
14

15. DECREASED COST AND TIME OF
CLINICAL DEVELOPMENT
NEW INDICATIONS
LOWER PRICE OF
THERAPY
ACCELERATED ACCESS
TO TREATMENT
MORE REAL-LIFE DATA
FURTHER DEVELOPMENT
FASTER APPROVAL
EARLY ACCESS
PASS - SCIENTIFIC & BUSINESS INTELLIGENCE
15

16. • Need for better design of clinical development
• Increased role of scientific consulting
• Changes in standard (study phases, endpoints)
• More flexible regulatory approach
• Significant increase in PASS interest
• PASS considered as an integral part of the drug development - planning
PASS during early phases of development
PASS - CRO PERSPECTIVE
16

17. ASK ??
?

18. THANK YOU
MAGDALENA MATUSIAK, MPharm
Pharmacovigilance Team Lead, KCR
e-mail: Magdalena.Matusiak@kcrcro.com